Department of Pharmacometrics and Pharmacokinetics, Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose, Tokyo, 204-8588, Japan.
Department of Microbiology, Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose, Tokyo, 204-8588, Japan.
Sci Rep. 2024 Jul 23;14(1):16931. doi: 10.1038/s41598-024-68248-3.
Pulmonary Mycobacterium avium-intracellulare complex (MAC) disease is a typical non-tuberculous mycobacterial infection. The incidence of pulmonary MAC is increasing worldwide. This study aimed to clarify the pharmacokinetic parameters of anti-pulmonary MAC disease drugs in silkworms. The pharmacokinetic parameters investigated included maximum concentration, area under the concentration-time curve, total clearance, and volume of distribution at steady-state. In addition, protein-binding rates, fat body transferability, and drug-drug interactions were examined. Antibiotic concentrations were measured using a validated high-performance liquid chromatography-mass spectrometry method. Among the antibiotics investigated, amikacin was not eliminated from silkworms during the 48-h observation period. In contrast, dose-proportional pharmacokinetics were observed in silkworms for all antibiotics tested, except for amikacin. Protein-binding rates in hemolymph for clarithromycin, azithromycin, rifampicin, ethambutol, and amikacin were 39.6 ± 3.0%, 39.5 ± 4.3%, 76.3 ± 3.2%, 20.9 ± 4.2%, and 73.1 ± 4.7%, respectively (mean ± standard deviation). The distribution of antibiotics in the fat bodies of silkworms was related to drug lipophilicity. No drug-drug interactions were observed in the silkworms. The pharmacokinetics of these drugs in silkworms differed significantly from those in humans. Therefore, while it is challenging to predict the pharmacokinetics of these drugs in humans based on silkworm data, the silkworm infection model has facilitated a comprehensive assessment of the relationship between antibiotic exposure and efficacy.
肺鸟分枝杆菌-胞内分枝杆菌复合群（MAC）病是一种典型的非结核分枝杆菌感染。全球范围内肺 MAC 的发病率正在上升。本研究旨在阐明抗肺 MAC 病药物在蚕体内的药代动力学参数。研究的药代动力学参数包括最大浓度、浓度-时间曲线下面积、总清除率和稳态分布容积。此外，还研究了蛋白结合率、脂肪体转移率和药物相互作用。采用经验证的高效液相色谱-质谱法测定抗生素浓度。在所研究的抗生素中，阿米卡星在 48 小时观察期内未从蚕体中消除。相比之下，除阿米卡星外，所有测试的抗生素在蚕体内均表现出剂量比例的药代动力学。克拉霉素、阿奇霉素、利福平、乙胺丁醇和阿米卡星在血淋巴中的蛋白结合率分别为 39.6 ± 3.0%、39.5 ± 4.3%、76.3 ± 3.2%、20.9 ± 4.2%和 73.1 ± 4.7%（平均值 ± 标准差）。抗生素在蚕脂肪体中的分布与药物脂溶性有关。在蚕体内未观察到药物相互作用。这些药物在蚕体内的药代动力学与人类有显著差异。因此，虽然根据蚕的数据预测这些药物在人体内的药代动力学具有挑战性，但蚕感染模型促进了对抗生素暴露与疗效之间关系的全面评估。
